Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD

治疗性抑制干性 AMD 中 Fas 介导的视网膜细胞死亡和炎症

• 批准号: 10093659
• 负责人: James T Handa
• 金额: $ 61.82万
• 依托单位: ONL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093659
• 关键词: Acute; Address; Age related macular degeneration; Aging; Anatomy; Antioxidants; Atrophic; Autophagocytosis; Biotechnology; Blindness; CD95 Antigens; Cause of Death; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Trials; Data; Decision Making; Development; Disease; Disease Progression; Dose; Effectiveness; Exhibits; Exposure to; Exudative age-related macular degeneration; Eye; Foundations; Fundus; Glaucoma; Healthcare; High Fat Diet; Histologic; Impairment; Individual; Inflammation; Inflammatory; Injections; Innovative Therapy; Institutes; Investments; Literature; Measures; Mediating; Microglia; Mitochondria; Modeling; Mus; Natural Immunity; Nonexudative age-related macular degeneration; Oryctolagus cuniculus; Outcome; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Patients; Peer Review; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Photoreceptors; Proteins; Quality of life; Reproducibility; Retina; Retinal Detachment; Retinal Diseases; Role; Safety; Schedule; Signal Transduction; Small Business Technology Transfer Research; Social Impacts; Societies; Solid; Stress; Structure of retinal pigment epithelium; Testing; Therapeutic; Time; Toxicology; United States; Visual; Vitamins; Work; advanced disease; baby boomer; biological adaptation to stress; cigarette smoke; cigarette smoke-induced; commercial application; commercialization; economic impact; effective therapy; effectiveness testing; exposure to cigarette smoke; gene therapy; geographic atrophy; human disease; improved; inhibitor/antagonist; interest; intravitreal injection; macrophage; macula; neuroprotection; novel; phase 2 study; preclinical development; prevent; recruit; response; retinal damage; safety study; treatment strategy; vector

PROJECT SUMMARY / ABSTRACT Age-related macular degeneration (AMD) is the leading, and due to the aging baby boomers, a growing cause of irreversible vision loss in the United States, and is strongly associated with exposure to cigarette smoke (CS) and high fat diets (HFD). While effective treatment is available for neovascular AMD, the AREDS II antioxidant vitamins are the only proven treatment for intermediate dry AMD. Unfortunately, AREDSII is not effective for early or late dry disease, and in intermediate AMD, it merely slows the progression to advanced disease. Treatments that target dry AMD will have a huge impact on the afflicted individual and save billions of health care dollars per year. Impairment of the oxidative stress response, autophagy, mitochondrial function, and the unfolded protein response, as well as dysregulated innate immunity have been implicated in AMD, and thus, have been investigated as treatment targets. Ultimately, these abnormalities cause death of retinal pigment epithelial (RPE) cells and photoreceptors (PR), leading to permanent vision loss. Fas-mediated cell death is the major mechanism of outer retinal cell loss in many retinal diseases including AMD. With no therapy to prevent Fas-mediated outer retinal cell death in AMD, a logical treatment strategy is to prevent Fas- mediated signaling, irrespective of the upstream impairment. ONL Therapeutics, an ophthalmic biotechnology company developing innovative therapies that prevent retinal cell death to improve visual outcomes for patients, has demonstrated the effectiveness of Fas inhibition in preventing retinal cell death in an acute model of AMD. Additionally, a gene therapy that inhibits Fas signaling has been developed and tested in acute and chronic models of glaucoma, wherein the vector provided significant inner retinal neuroprotection. Due to the role of Fas in AMD and the effect of Fas inhibition in protecting the retina following ocular stress, this proposal will examine the effect of the Fas inhibitors in acute and chronic models of atrophic AMD. Phase I of this Fast- track STTR proposal will i) determine the feasibility of using Fas inhibition to protect against acute CS-induced retinal damage, and ii) demonstrate that the duration of inhibition is clinically meaningful. Phase II will test the ocular safety and effectiveness of repeated intravitreal injections of our peptide Fas inhibitor. In addition, we will test the effectiveness of repeated intravitreal injections of the peptide Fas inhibitor as well as a single intravitreal injection of a Fas inhibitor vector in a novel, peer-reviewed chronic model of atrophic AMD in which apoB100 mice exposed to CS and HFD develop a geographic atrophy phenotype that closely resembles human disease. This proposal combines the expertise of ONL and the Wilmer Eye Institute to test these Fas inhibitors in models of atrophic AMD. Successful execution of the project will support the continued pre-clinical development of the Fas inhibitors for dry AMD and help attract additional investor interest in the company.

项目总结/摘要 视网膜相关性黄斑变性（AMD）是主要的，并且由于婴儿潮一代的老龄化， 在美国，不可逆转的视力丧失与吸烟密切相关。 (CS)高脂饮食（High Fat Diets，HFD）虽然新生血管性AMD可以获得有效的治疗，但AREDS II 抗氧化维生素是治疗中度干性AMD的唯一有效方法。不幸的是，AREDSII不是 对早期或晚期干性疾病有效，对于中期AMD，它只是减缓向晚期的进展 疾病针对干性AMD的治疗将对受折磨的个体产生巨大影响，并节省数十亿美元。 每年的医疗费用。氧化应激反应、自噬、线粒体功能受损， 未折叠的蛋白质反应以及先天免疫失调与AMD有关， 因此，已经作为治疗目标进行了研究。最终，这些异常会导致视网膜坏死。 色素上皮（RPE）细胞和光感受器（PR），导致永久性视力丧失。Fas介导细胞 死亡是包括AMD在内的许多视网膜疾病中外部视网膜细胞损失的主要机制。没有 为了预防AMD中Fas介导的外视网膜细胞死亡，合理的治疗策略是预防Fas- 介导的信号传导，而不管上游损伤。ONL Therapeutics，眼科生物技术 公司开发创新疗法，防止视网膜细胞死亡，以改善视力结果， 患者，已经证明了在急性模型中抑制Fas可以有效预防视网膜细胞死亡 关于AMD此外，已经开发了抑制Fas信号传导的基因疗法，并在急性和慢性炎症中进行了测试。 慢性青光眼模型，其中所述载体提供显著的内部视网膜神经保护。由于 Fas在AMD中的作用以及抑制Fas对眼应激后视网膜的保护作用， 将检查Fas抑制剂在萎缩性AMD的急性和慢性模型中的作用。第一阶段的快速- 跟踪STTR提案将i）确定使用Fas抑制来防止急性CS诱导的 视网膜损伤，和ii）证明抑制的持续时间在临床上是有意义的。第二阶段将测试 重复玻璃体内注射我们的肽Fas抑制剂的眼部安全性和有效性。另外我们 将测试重复玻璃体内注射肽Fas抑制剂以及单次注射的有效性。 在新的同行评议的萎缩性AMD慢性模型中玻璃体内注射Fas抑制剂载体，其中 暴露于CS和HFD的apoB 100小鼠出现地图状萎缩表型， 人类疾病。该提案结合了ONL和威尔默眼科研究所的专业知识来测试这些Fas 在萎缩性AMD模型中的抑制剂。该项目的成功执行将支持继续进行临床前 开发用于干性AMD的Fas抑制剂，并有助于吸引更多投资者对公司的兴趣。